Osteoarthritis is common in the aging population and results in cartilage degeneration. See Wang et al., Ann. N.Y. Acad. Sci., 2011, 1240 61-69. Characteristic features of osteoarthritis include changes in articular cartilage, chondrocyte hypertrophy, and increased remodeling of the periarticular bone. Acetaminophen is the first line treatment for osteoarthritis followed by non-steroidal anti-inflammatory drugs for mild to moderate symptoms. If disability is significant and anti-inflammatory drugs are ineffective, joint replacement surgery is typical. There is currently no effective disease-modifying treatment for osteoarthritis. Thus, there is a need to identify improved therapies.
Articular cartilage damage is an important pathologic feature leading to joint dysfunction. Articular cartilage is a reversibly compressible tissue that protects the underlying bones from biomechanical damage and is comprised mostly of collagen. The non-collagenous matrix is made up of proteoglycans. Chondrocytic cells are embedded in the matrix networks. They produce and maintain the cartilage by synthesizing and degrading matrix components. Mesenchymal precursor cells are involved with the development of mature articular cartilage and differentiate into chondrocytes.
Transforming growth factor beta (TGF-β) is a secreted protein that exists in different isoforms, e.g., TGF-β1, TGF-β2 and TGF-β3. TGF-β proteins effect cellular proliferation and differentiation. The TGF-β family is part of a superfamily of proteins known as the transforming growth factor beta superfamily which includes bone morphogenetic proteins. Davidson et al. report that reduced TGF-β signaling in cartilage has a role in impaired repair capacity. See Arthritis Research & Therapy, 2007, 7(6):R1338. Ballock et al., report the regulation of the expression of the type-II collagen gene by members of the TGF-β superfamily. See J Orthop Res, 1997, 15:463-467. Beuningen et al. report protection from interleukin 1 induced destruction of articular cartilage by TGF-β. See Ann Rheum Dis, 1993, 52:185-191.